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2. Single-cell CAR T atlas reveals type 2 function in 8-year leukaemia remission

Author

Bai, Zhiliang, Feng, Bing, McClory, Susan E., de Oliveira, Beatriz Coutinho, Diorio, Caroline, Gregoire, Céline, Tao, Bo, Yang, Luojia, Zhao, Ziran, Peng, Lei, Sferruzza, Giacomo, Zhou, Liqun, Zhou, Xiaolei, Kerr, Jessica, Baysoy, Alev, Su, Graham, Yang, Mingyu, Camara, Pablo G., Chen, Sidi, Tang, Li, June, Carl H., Melenhorst, J. Joseph, Grupp, Stephan A., and Fan, Rong

Published
2024
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5. Adoptive cellular therapy after hematopoietic stem cell transplantation

Author

Vittayawacharin, Pongthep, Kongtim, Piyanuch, Chu, Yaya, June, Carl H, Bollard, Catherine M, and Ciurea, Stefan O

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Stem Cell Research - Nonembryonic - Human, Cancer, Biotechnology, Stem Cell Research, Regenerative Medicine, Transplantation, 6.2 Cellular and gene therapies, Development of treatments and therapeutic interventions, 5.2 Cellular and gene therapies, Evaluation of treatments and therapeutic interventions, Cardiorespiratory Medicine and Haematology, Cardiovascular medicine and haematology
Abstract

Effective cellular therapy using CD19 chimeric antigen receptor T-cells for the treatment of advanced B-cell malignancies raises the question of whether the administration of adoptive cellular therapy (ACT) posttransplant could reduce relapse and improve survival. Moreover, several early phase clinical studies have shown the potential beneficial effects of administration of tumor-associated antigen-specific T-cells and natural killer cells posttransplant for high-risk patients, aiming to decrease relapse and possibly improve survival. In this article, we present an in-depth review of ACT after transplantation, which has the potential to significantly improve the efficacy of this procedure and revolutionize this field.

Published
2024

6. Mitigation of chromosome loss in clinical CRISPR-Cas9-engineered T cells

Author

Tsuchida, Connor A, Brandes, Nadav, Bueno, Raymund, Trinidad, Marena, Mazumder, Thomas, Yu, Bingfei, Hwang, Byungjin, Chang, Christopher, Liu, Jamin, Sun, Yang, Hopkins, Caitlin R, Parker, Kevin R, Qi, Yanyan, Hofman, Laura, Satpathy, Ansuman T, Stadtmauer, Edward A, Cate, Jamie HD, Eyquem, Justin, Fraietta, Joseph A, June, Carl H, Chang, Howard Y, Ye, Chun Jimmie, and Doudna, Jennifer A

Subjects
Biomedical and Clinical Sciences, Immunology, Genetics, Clinical Research, Gene Therapy, Biotechnology, Bioengineering, 5.2 Cellular and gene therapies, 5.1 Pharmaceuticals, Generic health relevance, Cancer, Humans, Chromosomes, CRISPR-Cas Systems, DNA Damage, Gene Editing, T-Lymphocytes, Clinical Trials as Topic, Chromosome Aberrations, CAR T cells, CRISPR screen, CRISPR-Cas9, DNA repair, T cells, aneuploidy, chromosome loss, clinical trial, genome editing, immunoengineering, genome editing&#x3a, CAR T cells, Biological Sciences, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

CRISPR-Cas9 genome editing has enabled advanced T cell therapies, but occasional loss of the targeted chromosome remains a safety concern. To investigate whether Cas9-induced chromosome loss is a universal phenomenon and evaluate its clinical significance, we conducted a systematic analysis in primary human T cells. Arrayed and pooled CRISPR screens revealed that chromosome loss was generalizable across the genome and resulted in partial and entire loss of the targeted chromosome, including in preclinical chimeric antigen receptor T cells. T cells with chromosome loss persisted for weeks in culture, implying the potential to interfere with clinical use. A modified cell manufacturing process, employed in our first-in-human clinical trial of Cas9-engineered T cells (NCT03399448), reduced chromosome loss while largely preserving genome editing efficacy. Expression of p53 correlated with protection from chromosome loss observed in this protocol, suggesting both a mechanism and strategy for T cell engineering that mitigates this genotoxicity in the clinic.

Published
2023

11. Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results

Author

Bagley, Stephen J., Logun, Meghan, Fraietta, Joseph A., Wang, Xin, Desai, Arati S., Bagley, Linda J., Nabavizadeh, Ali, Jarocha, Danuta, Martins, Rene, Maloney, Eileen, Lledo, Lester, Stein, Carly, Marshall, Amy, Leskowitz, Rachel, Jadlowsky, Julie K., Christensen, Shannon, Oner, Bike Su, Plesa, Gabriela, Brennan, Andrea, Gonzalez, Vanessa, Chen, Fang, Sun, Yusha, Gladney, Whitney, Barrett, David, Nasrallah, MacLean P., Hwang, Wei-Ting, Ming, Guo-Li, Song, Hongjun, Siegel, Donald L., June, Carl H., Hexner, Elizabeth O., Binder, Zev A., and O’Rourke, Donald M.

Published
2024
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12. T cell lymphoma and secondary primary malignancy risk after commercial CAR T cell therapy

Author

Ghilardi, Guido, Fraietta, Joseph A., Gerson, James N., Van Deerlin, Vivianna M., Morrissette, Jennifer J. D., Caponetti, Gabriel C., Paruzzo, Luca, Harris, Jaryse C., Chong, Elise A., Susanibar Adaniya, Sandra P., Svoboda, Jakub, Nasta, Sunita D., Ugwuanyi, Ositadimma H., Landsburg, Daniel J., Fardella, Eugenio, Waxman, Adam J., Chong, Emeline R., Patel, Vrutti, Pajarillo, Raymone, Kulikovskaya, Irina, Lieberman, David B., Cohen, Adam D., Levine, Bruce L., Stadtmauer, Edward A., Frey, Noelle V., Vogl, Dan T., Hexner, Elizabeth O., Barta, Stefan K., Porter, David L., Garfall, Alfred L., Schuster, Stephen J., June, Carl H., and Ruella, Marco

Published
2024
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14. Potentiating adoptive cell therapy using synthetic IL-9 receptors

Author

Kalbasi, Anusha, Siurala, Mikko, Su, Leon L, Tariveranmoshabad, Mito, Picton, Lora K, Ravikumar, Pranali, Li, Peng, Lin, Jian-Xin, Escuin-Ordinas, Helena, Da, Tong, Kremer, Sarah V, Sun, Amy L, Castelli, Sofia, Agarwal, Sangya, Scholler, John, Song, Decheng, Rommel, Philipp C, Radaelli, Enrico, Young, Regina M, Leonard, Warren J, Ribas, Antoni, June, Carl H, and Garcia, K Christopher

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Immunology, Oncology and Carcinogenesis, Vaccine Related, Cancer, 5.2 Cellular and gene therapies, Development of treatments and therapeutic interventions, Animals, Cell- and Tissue-Based Therapy, Immunotherapy, Adoptive, Interleukin Receptor Common gamma Subunit, Interleukins, Melanoma, Mice, Neoplasms, Pancreatic Neoplasms, Receptors, Interleukin-9, Recombinant Fusion Proteins, STAT Transcription Factors, T-Lymphocytes, General Science & Technology
Abstract

Synthetic receptor signalling has the potential to endow adoptively transferred T cells with new functions that overcome major barriers in the treatment of solid tumours, including the need for conditioning chemotherapy1,2. Here we designed chimeric receptors that have an orthogonal IL-2 receptor extracellular domain (ECD) fused with the intracellular domain (ICD) of receptors for common γ-chain (γc) cytokines IL-4, IL-7, IL-9 and IL-21 such that the orthogonal IL-2 cytokine elicits the corresponding γc cytokine signal. Of these, T cells that signal through the chimeric orthogonal IL-2Rβ-ECD-IL-9R-ICD (o9R) are distinguished by the concomitant activation of STAT1, STAT3 and STAT5 and assume characteristics of stem cell memory and effector T cells. Compared to o2R T cells, o9R T cells have superior anti-tumour efficacy in two recalcitrant syngeneic mouse solid tumour models of melanoma and pancreatic cancer and are effective even in the absence of conditioning lymphodepletion. Therefore, by repurposing IL-9R signalling using a chimeric orthogonal cytokine receptor, T cells gain new functions, and this results in improved anti-tumour activity for hard-to-treat solid tumours.

Published
2022

18. Reinfusion of CD19 CAR T cells for relapse prevention and treatment in children with acute lymphoblastic leukemia

Author

Myers, Regina M., Devine, Kaitlin, Li, Yimei, Lawrence, Sophie, Leahy, Allison Barz, Liu, Hongyan, Vernau, Lauren, Callahan, Colleen, Baniewicz, Diane, Kadauke, Stephan, McGuire, Regina, Wertheim, Gerald B., Kulikovskaya, Irina, Gonzalez, Vanessa E., Fraietta, Joseph A., DiNofia, Amanda M., Hunger, Stephen P., Rheingold, Susan R., Aplenc, Richard, June, Carl H., Grupp, Stephan A., Wray, Lisa, and Maude, Shannon L.

Published
2024
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19. Long-term stability of clinical-grade lentiviral vectors for cell therapy

Author

Jadlowsky, Julie K., Leskowitz, Rachel, McKenna, Stephen, Karar, Jayashree, Ma, Yujie, Dai, Anlan, Plesa, Gabriela, Chen, Fang, Alexander, Kathleen, Petrella, Jennifer, Gong, Nan, Hwang, Wei-Ting, Farrelly, Olivia, Barber-Rotenberg, Julie, Christensen, Shannon, Gonzalez, Vanessa E., Chew, Anne, Fraietta, Joseph A., and June, Carl H.

Published
2024
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22. An NK-like CAR T cell transition in CAR T cell dysfunction

Author

Good, Charly R, Aznar, M Angela, Kuramitsu, Shunichiro, Samareh, Parisa, Agarwal, Sangya, Donahue, Greg, Ishiyama, Kenichi, Wellhausen, Nils, Rennels, Austin K, Ma, Yujie, Tian, Lifeng, Guedan, Sonia, Alexander, Katherine A, Zhang, Zhen, Rommel, Philipp C, Singh, Nathan, Glastad, Karl M, Richardson, Max W, Watanabe, Keisuke, Tanyi, Janos L, O'Hara, Mark H, Ruella, Marco, Lacey, Simon F, Moon, Edmund K, Schuster, Stephen J, Albelda, Steven M, Lanier, Lewis L, Young, Regina M, Berger, Shelley L, and June, Carl H

Subjects
Rare Diseases, Genetics, Gene Therapy, Biotechnology, Cancer, 2.1 Biological and endogenous factors, Aetiology, Animals, CD8-Positive T-Lymphocytes, Cell Line, Tumor, HEK293 Cells, Humans, Immunotherapy, Adoptive, Inhibitor of Differentiation Proteins, Male, Mice, Mice, Knockout, Mice, Nude, Mice, SCID, Neoplasm Proteins, Pancreatic Neoplasms, Receptors, Chimeric Antigen, SOXC Transcription Factors, CAR T cell, ID3, NK-like T cell, SOX4, T cell dysfunction, T cell exhaustion, cancer, cell transfer therapy, immunology, immunotherapy, pancreatic cancer, single-cell RNA-seq, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematological malignancies but remains ineffective in solid tumors, due in part to CAR T cell exhaustion in the solid tumor microenvironment. To study dysfunction of mesothelin-redirected CAR T cells in pancreatic cancer, we establish a robust model of continuous antigen exposure that recapitulates hallmark features of T cell exhaustion and discover, both in vitro and in CAR T cell patients, that CAR dysregulation is associated with a CD8+ T-to-NK-like T cell transition. Furthermore, we identify a gene signature defining CAR and TCR dysregulation and transcription factors, including SOX4 and ID3 as key regulators of CAR T cell exhaustion. Our findings shed light on the plasticity of human CAR T cells and demonstrate that genetic downmodulation of ID3 and SOX4 expression can improve the efficacy of CAR T cell therapy in solid tumors by preventing or delaying CAR T cell dysfunction.

Published
2021

26. Deletion of the inhibitory co-receptor CTLA-4 enhances and invigorates chimeric antigen receptor T cells

Author

Agarwal, Sangya, Aznar, M. Angela, Rech, Andrew J., Good, Charly R., Kuramitsu, Shunichiro, Da, Tong, Gohil, Mercy, Chen, Linhui, Hong, Seok-Jae Albert, Ravikumar, Pranali, Rennels, Austin K., Salas-Mckee, January, Kong, Weimin, Ruella, Marco, Davis, Megan M., Plesa, Gabriela, Fraietta, Joseph A., Porter, David L., Young, Regina M., and June, Carl H.

Published
2023
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29. Dual Targeting of Mesothelin and CD19 with Chimeric Antigen Receptor-Modified T Cells in Patients with Metastatic Pancreatic Cancer

Author

Ko, Andrew H, Jordan, Alexander C, Tooker, Evan, Lacey, Simon F, Chang, Renee B, Li, Yan, Venook, Alan P, Tempero, Margaret, Damon, Lloyd, Fong, Lawrence, O'Hara, Mark H, Levine, Bruce L, Melenhorst, J Joseph, Plesa, Gabriela, June, Carl H, and Beatty, Gregory L

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Cancer, Gene Therapy, Genetics, Rare Diseases, Pancreatic Cancer, Vaccine Related, Prevention, Digestive Diseases, 5.2 Cellular and gene therapies, Development of treatments and therapeutic interventions, Antigens, CD19, GPI-Linked Proteins, Humans, Immunotherapy, Adoptive, Lymphocyte Depletion, Mesothelin, Neoplasm Metastasis, Neoplasm Staging, Pancreatic Neoplasms, Pilot Projects, Receptors, Chimeric Antigen, T-Lymphocytes, Treatment Outcome, B cells, CD19, chimeric antigen receptor, mesothelin, pancreatic cancer, Biological Sciences, Technology, Medical and Health Sciences, Biotechnology, Clinical sciences, Medical biotechnology
Abstract

B cells infiltrate pancreatic ductal adenocarcinoma (PDAC) and in preclinical cancer models, can suppress T cell immunosurveillance in cancer. Here, we conducted a pilot study to assess the safety and feasibility of administering lentiviral-transduced chimeric antigen receptor (CAR)-modified autologous T cells redirected against mesothelin to target tumor cells along with CART cells redirected against CD19 to deplete B cells. Both CARs contained 4-1BB and CD3ζ signaling domains. Three patients with chemotherapy-refractory PDAC received 1.5 g/m2 cyclophosphamide prior to separate infusions of lentiviral-transduced T cells engineered to express chimeric anti-mesothelin immunoreceptor SS1 (CART-Meso, 3 × 107/m2) and chimeric anti-CD19 immunoreceptor (CART-19, 3 × 107/m2). Treatment was well tolerated without dose-limiting toxicities. Best response was stable disease (1 of 3 patients). CART-19 (compared to CART-Meso) cells showed the greatest expansion in the blood, although persistence was transient. B cells were successfully depleted in all subjects, became undetectable by 7-10 days post-infusion, and remained undetectable for at least 28 days. Together, concomitant delivery of CART-Meso and CART-19 cells in patients with PDAC is safe. CART-19 cells deplete normal B cells but at the dose tested in these 3 subjects did not improve CART-Meso cell persistence.

Published
2020

30. Single-Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies

Author

Parker, Kevin R, Migliorini, Denis, Perkey, Eric, Yost, Kathryn E, Bhaduri, Aparna, Bagga, Puneet, Haris, Mohammad, Wilson, Neil E, Liu, Fang, Gabunia, Khatuna, Scholler, John, Montine, Thomas J, Bhoj, Vijay G, Reddy, Ravinder, Mohan, Suyash, Maillard, Ivan, Kriegstein, Arnold R, June, Carl H, Chang, Howard Y, Posey, Avery D, and Satpathy, Ansuman T

Subjects
Biomedical and Clinical Sciences, Immunology, Immunization, Neurosciences, Vaccine Related, Rare Diseases, Biotechnology, Genetics, Aetiology, 2.1 Biological and endogenous factors, Development of treatments and therapeutic interventions, 5.2 Cellular and gene therapies, Neurological, Animals, Antibodies, Bispecific, Antigens, CD19, B-Lymphocytes, Blood-Brain Barrier, Brain, Cell Line, Tumor, Cytotoxicity, Immunologic, Epithelial Cells, Humans, Immunotherapy, Immunotherapy, Adoptive, Mice, Mice, Inbred NOD, Mice, SCID, Muscle, Smooth, Vascular, Neoplasms, Receptors, Antigen, T-Cell, Receptors, Chimeric Antigen, Single-Cell Analysis, T-Lymphocytes, Xenograft Model Antitumor Assays, Biological Sciences, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

CD19-directed immunotherapies are clinically effective for treating B cell malignancies but also cause a high incidence of neurotoxicity. A subset of patients treated with chimeric antigen receptor (CAR) T cells or bispecific T cell engager (BiTE) antibodies display severe neurotoxicity, including fatal cerebral edema associated with T cell infiltration into the brain. Here, we report that mural cells, which surround the endothelium and are critical for blood-brain-barrier integrity, express CD19. We identify CD19 expression in brain mural cells using single-cell RNA sequencing data and confirm perivascular staining at the protein level. CD19 expression in the brain begins early in development alongside the emergence of mural cell lineages and persists throughout adulthood across brain regions. Mouse mural cells demonstrate lower levels of Cd19 expression, suggesting limitations in preclinical animal models of neurotoxicity. These data suggest an on-target mechanism for neurotoxicity in CD19-directed therapies and highlight the utility of human single-cell atlases for designing immunotherapies.

Published
2020

31. Modulation of the gut microbiota engages antigen cross-presentation to enhance antitumor effects of CAR T cell immunotherapy

Author

Uribe-Herranz, Mireia, Beghi, Silvia, Ruella, Marco, Parvathaneni, Kalpana, Salaris, Silvano, Kostopoulos, Nektarios, George, Subin S., Pierini, Stefano, Krimitza, Elisavet, Costabile, Francesca, Ghilardi, Guido, Amelsberg, Kimberly V., Lee, Yong Gu, Pajarillo, Raymone, Markmann, Caroline, McGettigan-Croce, Bevin, Agarwal, Divyansh, Frey, Noelle, Lacey, Simon F., Scholler, John, Gabunia, Khatuna, Wu, Gary, Chong, Elise, Porter, David L., June, Carl H., Schuster, Stephen J., Bhoj, Vijay, and Facciabene, Andrea

Published
2023
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32. Impact of poverty and neighborhood opportunity on outcomes for children treated with CD19-directed CAR T-cell therapy

Author

Newman, Haley, Li, Yimei, Liu, Hongyan, Myers, Regina M., Tam, Vicky, DiNofia, Amanda, Wray, Lisa, Rheingold, Susan R., Callahan, Colleen, White, Claire, Baniewicz, Diane, Winestone, Lena E., Kadauke, Stephan, Diorio, Caroline, June, Carl H., Getz, Kelly D., Aplenc, Richard, Teachey, David T., Maude, Shannon L., Grupp, Stephan A., Bona, Kira, and Leahy, Allison Barz

Published
2023
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33. Two cases of severe pulmonary toxicity from highly active mesothelin-directed CAR T cells

Author

Haas, Andrew R., Golden, Ryan J., Litzky, Leslie A., Engels, Boris, Zhao, Linlin, Xu, Fangmin, Taraszka, John A., Ramones, Melissa, Granda, Brian, Chang, Wan-Jung, Jadlowsky, Julie, Shea, Kim-Marie, Runkle, Adam, Chew, Anne, Dowd, Emily, Gonzalez, Vanessa, Chen, Fang, Liu, Xiaojun, Fang, Chongyun, Jiang, Shuguang, Davis, Megan M., Sheppard, Neil C., Zhao, Yangbing, Fraietta, Joseph A., Lacey, Simon F., Plesa, Gabriela, Melenhorst, J. Joseph, Mansfield, Keith, Brogdon, Jennifer L., Young, Regina M., Albelda, Steven M., June, Carl H., and Tanyi, Janos L.

Published
2023
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35. Author Correction: Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy

Author

Smith, Melody, Dai, Anqi, Ghilardi, Guido, Amelsberg, Kimberly V., Devlin, Sean M., Pajarillo, Raymone, Slingerland, John B., Beghi, Silvia, Herrera, Pamela S., Giardina, Paul, Clurman, Annelie, Dwomoh, Emmanuel, Armijo, Gabriel, Gomes, Antonio L. C., Littmann, Eric R., Schluter, Jonas, Fontana, Emily, Taur, Ying, Park, Jae H., Palomba, Maria Lia, Halton, Elizabeth, Ruiz, Josel, Jain, Tania, Pennisi, Martina, Afuye, Aishat Olaide, Perales, Miguel-Angel, Freyer, Craig W., Garfall, Alfred, Gier, Shannon, Nasta, Sunita, Landsburg, Daniel, Gerson, James, Svoboda, Jakub, Cross, Justin, Chong, Elise A., Giralt, Sergio, Gill, Saar I., Riviere, Isabelle, Porter, David L., Schuster, Stephen J., Sadelain, Michel, Frey, Noelle, Brentjens, Renier J., June, Carl H., Pamer, Eric G., Peled, Jonathan U., Facciabene, Andrea, van den Brink, Marcel R. M., and Ruella, Marco

Published
2023
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36. Expression of inducible factors reprograms CAR-T cells for enhanced function and safety

Author

Smole, Anže, Benton, Alexander, Poussin, Mathilde A., Eiva, Monika A., Mezzanotte, Claudia, Camisa, Barbara, Greco, Beatrice, Sharma, Prannda, Minutolo, Nicholas G., Gray, Falon, Bear, Adham S., Baroja, Miren L., Cummins, Casey, Xu, Chong, Sanvito, Francesca, Goldgewicht, Andrea Lang, Blanchard, Tatiana, Rodriguez-Garcia, Alba, Klichinsky, Michael, Bonini, Chiara, June, Carl H., Posey, Avery D., Jr., Linette, Gerald P., Carreno, Beatriz M., Casucci, Monica, and Powell, Daniel J., Jr.

Published
2022
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37. Anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia

Author

Gill, Saar, Vides, Vanessa, Frey, Noelle V., Hexner, Elizabeth O., Metzger, Susan, O'Brien, Megan, Hwang, Wei-Ting, Brogdon, Jennifer L., Davis, Megan M., Fraietta, Joseph A., Gaymon, Avery L., Gladney, Whitney L., Lacey, Simon F., Lamontagne, Anne, Mato, Anthony R., Maus, Marcela V., Melenhorst, J. Joseph, Pequignot, Edward, Ruella, Marco, Shestov, Maksim, Byrd, John C., Schuster, Stephen J., Siegel, Donald L., Levine, Bruce L., June, Carl H., and Porter, David L.

Published
2022
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39. PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial

Author

Narayan, Vivek, Barber-Rotenberg, Julie S., Jung, In-Young, Lacey, Simon F., Rech, Andrew J., Davis, Megan M., Hwang, Wei-Ting, Lal, Priti, Carpenter, Erica L., Maude, Shannon L., Plesa, Gabriela, Vapiwala, Neha, Chew, Anne, Moniak, Michael, Sebro, Ronnie A., Farwell, Michael D., Marshall, Amy, Gilmore, Joan, Lledo, Lester, Dengel, Karen, Church, Sarah E., Hether, Tyler D., Xu, Jun, Gohil, Mercy, Buckingham, Thomas H., Yee, Stephanie S., Gonzalez, Vanessa E., Kulikovskaya, Irina, Chen, Fang, Tian, Lifeng, Tien, Kyle, Gladney, Whitney, Nobles, Christopher L., Raymond, Hayley E., Hexner, Elizabeth O., Siegel, Donald L., Bushman, Frederic D., June, Carl H., Fraietta, Joseph A., and Haas, Naomi B.

Published
2022
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41. Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy

Author

Smith, Melody, Dai, Anqi, Ghilardi, Guido, Amelsberg, Kimberly V., Devlin, Sean M., Pajarillo, Raymone, Slingerland, John B., Beghi, Silvia, Herrera, Pamela S., Giardina, Paul, Clurman, Annelie, Dwomoh, Emmanuel, Armijo, Gabriel, Gomes, Antonio L. C., Littmann, Eric R., Schluter, Jonas, Fontana, Emily, Taur, Ying, Park, Jae H., Palomba, Maria Lia, Halton, Elizabeth, Ruiz, Josel, Jain, Tania, Pennisi, Martina, Afuye, Aishat Olaide, Perales, Miguel-Angel, Freyer, Craig W., Garfall, Alfred, Gier, Shannon, Nasta, Sunita, Landsburg, Daniel, Gerson, James, Svoboda, Jakub, Cross, Justin, Chong, Elise A., Giralt, Sergio, Gill, Saar I., Riviere, Isabelle, Porter, David L., Schuster, Stephen J., Sadelain, Michel, Frey, Noelle, Brentjens, Renier J., June, Carl H., Pamer, Eric G., Peled, Jonathan U., Facciabene, Andrea, van den Brink, Marcel R. M., and Ruella, Marco

Published
2022
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42. A randomized phase 2 trial of idiotype vaccination and adoptive autologous T-cell transfer in patients with multiple myeloma

Author

Qazilbash, Muzaffar H., Saini, Neeraj Y., Cha, Soung-chul, Wang, Zhe, Stadtmauer, Edward A., Baladandayuthapani, Veerabhadran, Lin, Heather, Tross, Beryl, Honhar, Medhavi, Rao, Sheetal S., Kim, Kunhwa, Popescu, Michael, Szymura, Szymon, Zhang, Tiantian, Anderson, Aaron, Bashir, Qaiser, Shpall, Elizabeth J., Orlowski, Robert Z., Levine, Bruce L., Kerr, Naseem, Garfall, Alfred, Cohen, Adam, Vogl, Dan T., Dengel, Karen, June, Carl H., Champlin, Richard, and Kwak, Larry W.

Published
2022
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43. Decade-long leukaemia remissions with persistence of CD4+ CAR T cells

Author

Melenhorst, J. Joseph, Chen, Gregory M., Wang, Meng, Porter, David L., Chen, Changya, Collins, McKensie A., Gao, Peng, Bandyopadhyay, Shovik, Sun, Hongxing, Zhao, Ziran, Lundh, Stefan, Pruteanu-Malinici, Iulian, Nobles, Christopher L., Maji, Sayantan, Frey, Noelle V., Gill, Saar I., Loren, Alison W., Tian, Lifeng, Kulikovskaya, Irina, Gupta, Minnal, Ambrose, David E., Davis, Megan M., Fraietta, Joseph A., Brogdon, Jennifer L., Young, Regina M., Chew, Anne, Levine, Bruce L., Siegel, Donald L., Alanio, Cécile, Wherry, E. John, Bushman, Frederic D., Lacey, Simon F., Tan, Kai, and June, Carl H.

Published
2022
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45. Antigen Presenting Cell Mimetic Lipid Nanoparticles for Rapid mRNA CAR T Cell Cancer Immunotherapy

Author

Metzloff, Ann E., primary, Padilla, Marshall S., additional, Gong, Ningqiang, additional, Billingsley, Margaret M., additional, Han, Xuexiang, additional, Merolle, Maria, additional, Mai, David, additional, Figueroa‐Espada, Christian G., additional, Thatte, Ajay S., additional, Haley, Rebecca M., additional, Mukalel, Alvin J., additional, Hamilton, Alex G., additional, Alameh, Mohamad‐Gabriel, additional, Weissman, Drew, additional, Sheppard, Neil C., additional, June, Carl H., additional, and Mitchell, Michael J., additional

Published
2024
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49. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma

Author

O'Rourke, Donald M, Nasrallah, MacLean P, Desai, Arati, Melenhorst, Jan J, Mansfield, Keith, Morrissette, Jennifer JD, Martinez-Lage, Maria, Brem, Steven, Maloney, Eileen, Shen, Angela, Isaacs, Randi, Mohan, Suyash, Plesa, Gabriela, Lacey, Simon F, Navenot, Jean-Marc, Zheng, Zhaohui, Levine, Bruce L, Okada, Hideho, June, Carl H, Brogdon, Jennifer L, and Maus, Marcela V

Subjects
Neurosciences, Immunization, Cancer, Rare Diseases, Brain Cancer, Biotechnology, Brain Disorders, Stem Cell Research - Nonembryonic - Human, Stem Cell Research, Clinical Research, Vaccine Related, Development of treatments and therapeutic interventions, 5.2 Cellular and gene therapies, Aged, Brain Neoplasms, Cell- and Tissue-Based Therapy, ErbB Receptors, Female, Glioblastoma, Humans, Immunohistochemistry, Immunotherapy, Adoptive, Male, Middle Aged, Neoplasm Recurrence, Local, Receptors, Antigen, T-Cell, Biological Sciences, Medical and Health Sciences
Abstract

We conducted a first-in-human study of intravenous delivery of a single dose of autologous T cells redirected to the epidermal growth factor receptor variant III (EGFRvIII) mutation by a chimeric antigen receptor (CAR). We report our findings on the first 10 recurrent glioblastoma (GBM) patients treated. We found that manufacturing and infusion of CAR-modified T cell (CART)-EGFRvIII cells are feasible and safe, without evidence of off-tumor toxicity or cytokine release syndrome. One patient has had residual stable disease for over 18 months of follow-up. All patients demonstrated detectable transient expansion of CART-EGFRvIII cells in peripheral blood. Seven patients had post-CART-EGFRvIII surgical intervention, which allowed for tissue-specific analysis of CART-EGFRvIII trafficking to the tumor, phenotyping of tumor-infiltrating T cells and the tumor microenvironment in situ, and analysis of post-therapy EGFRvIII target antigen expression. Imaging findings after CART immunotherapy were complex to interpret, further reinforcing the need for pathologic sampling in infused patients. We found trafficking of CART-EGFRvIII cells to regions of active GBM, with antigen decrease in five of these seven patients. In situ evaluation of the tumor environment demonstrated increased and robust expression of inhibitory molecules and infiltration by regulatory T cells after CART-EGFRvIII infusion, compared to pre-CART-EGFRvIII infusion tumor specimens. Our initial experience with CAR T cells in recurrent GBM suggests that although intravenous infusion results in on-target activity in the brain, overcoming the adaptive changes in the local tumor microenvironment and addressing the antigen heterogeneity may improve the efficacy of EGFRvIII-directed strategies in GBM.

Published
2017

50. Is autoimmunity the Achilles' heel of cancer immunotherapy?

Author

June, Carl H, Warshauer, Jeremy T, and Bluestone, Jeffrey A

Subjects
T-Lymphocytes, Humans, Neoplasms, Autoimmune Diseases, Antineoplastic Agents, Immunologic Factors, Antibodies, Monoclonal, Immunotherapy, Adoptive Transfer, Autoimmunity, Tumor Escape, CTLA-4 Antigen, Programmed Cell Death 1 Receptor, Autoimmune Hypophysitis, Ipilimumab, Immunology, Medical and Health Sciences
Abstract

The emergence of immuno-oncology as the first broadly successful strategy for metastatic cancer will require clinicians to integrate this new pillar of medicine with chemotherapy, radiation, and targeted small-molecule compounds. Of equal importance is gaining an understanding of the limitations and toxicities of immunotherapy. Immunotherapy was initially perceived to be a relatively less toxic approach to cancer treatment than other available therapies-and surely it is, when compared to those. However, as the use of immunotherapy becomes more common, especially as first- and second-line treatments, immunotoxicity and autoimmunity are emerging as the Achilles' heel of immunotherapy. In this Perspective, we discuss evidence that the occurrence of immunotoxicity bodes well for the patient, and describe mechanisms that might be related to the induction of autoimmunity. We then explore approaches to limit immunotoxicity, and discuss the future directions of research and reporting that are needed to diminish it.

Published
2017

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